facts and hypotheses about dna methylation dna methylation and gene regulation (1990). edited by r....

2
tion of sex steroid receptors. Both have made many contributions to the field and their respective groups have formed or developed the research careers of many of those now publishing in steroid endocrinology and related fields. It is most appropriate, therefore, that a book should now appear to report on a conference held in their joint honour. The book starts with two entertaining reviews of the work of Gorski and Jensen - fascinating reading for those involved and historically illuminating for all. There follows a section on the structure and function of the individual steroid receptors. These chapters are easily read and give an interesting reflection of the similarities and differences of the various receptors. It has been clear for a long time that changes in conformation are critical to the function of steroid receptor complexes. The Chapters by Smith, Mendel, Pratt and Auricchio bring us well up to date in this field, being particularly good in defining the interaction of steroid receptors with heat shock protein-90 (originally thought by many to be an artifact but now assuming real importance as a possible regulatory mechanism) and reviewing the physiological significance of tyrosine phosphorylation in steroid receptor function. For those not strictly interested in steroid endocrin- ology, steroid receptors have had great appeal in two quite separate fields. Firstly, steroid receptors, perhaps more than any other molecule, have given us good information on the control of gene expression in animals. Secondly, steroid receptors have given both prognostic clinical information and the basis for new types of therapy for breast and other steroid hormone sensitive cancers. Readers are provided with several good chapters in both areas. The Chapter by Lannigan and Notides gives a particularly nice view of the 3- dimensional implications of steroid receptor/DNA interaction. One of the most interesting, and rapidly expanding, areas of the steroid receptor industry is the investigation of steroid/growth factor interaction. The Chapter by Stance1 whets the appetite and points the direction for several new research projects. The Chapter from Lippman’s group nicely crosses the bridge from biology to clinic by demonstrating the potential of steroid receptor/growth factor interac- tion to explain the clinical course of breast cancer and suggests how this understanding may lead to improved therapies. The prognostic value of steroid receptors is reviewed by McCarty and new approaches to therapy, such as ‘receptor-directed radiotherapy’ are discussed at the end. Overall, Sat0 and Stevens have organised this book into an entertaining and very valuable source of information. I feel that it will retain its interest and value for several years and I hope that it will be read by all involved in research in steroid endocrinology, control of gene expression and treatment of breast, gynaecological and prostate cancer. Robin Leake is in the Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK. Facts and Hypotheses about DNA Methylation DNA Methylation and Gene Regulation (1990). Edited by R. HOLLIDAY, M. MONK AND J. E. PUGH. The Royal Society: London. 161pp. f35. By Peter Karran This volume contains the proceedings of a Discussion Meeting gathered to consider the question of how (or if) methylation of cytosine in DNA regulates gene expression. Epigenetic control of gene expression is clearly a fairly widespread phenomenon and methyl- ation appears to represent the best bet for the underlying mechanism. Although the correlation be- tween high levels of cytosine methylation and reduced transcription have been around for a number of years, enough frustrating exceptions have remained for each of its detailed aspects to prevent general acceptance of a causal relationship between the two phenomena. The authors of the 14 papers which make up this book confront these exceptions in a generally interesting way, although no truly new light is shed on the possible detailed mechanisms of gene repression by methyl- ation. The scope of the book ranges from a consideration of the possible evolution of methylation as a transcrip- tional repressor for these assorted irrelevant DNA sequences acquired as a consequence of relentless genome expansion to the more common demon- strations of inverse correlations between the levels of cytosine methylation and transcriptional activity. Exemplifying the exceptions to what few general rules have been formulated is the observation that methyl- ation-free CpG islands are not confined to the promoter regions of universally expressed housekeeping genes but may also occur in those of genes expressed in a tissue-specific fashion (Edwards). Also considered (Mehan et al.) are DNA-binding proteins which are methylation-specific but not sequence-specific and which might bind to ‘junk’ DNA, thereby reducing the amount of DNA to be monitored by more fastidious transcription factors. Inactivation of transfected DNA sequences, which is one of the cornerstones of the argument relating methylation in the control of transcription, is also represented here. A series of analogous experiments are described (Frank et al.) in which transfected methylated IgG K genes are ex- pressed only in mature lymphocytes, and are presented as evidence that demethylation is developmentally regulated. There are also two papers which address the question of chromosomal imprinting in mammals in relation to differential methylation patterns in maternal and paternal genes (Monk, Surani). Implicit through- out all the contributions is the idea that methylation is perhaps not the whole story and that some second control system is involved in methylation-related inactivation of transcription. An intriguing possibility is raised (Riggs) that the CpG methylation-associated inactivation of the X-chromosome (perhaps the best

Upload: peter-karran

Post on 06-Jun-2016

213 views

Category:

Documents


1 download

TRANSCRIPT

Page 1: Facts and hypotheses about DNA methylation DNA Methylation and Gene Regulation (1990). Edited by R. Holliday, M. Monk and J. E. Pugh. The Royal Society: London. 161pp. £35

tion of sex steroid receptors. Both have made many contributions to the field and their respective groups have formed or developed the research careers of many of those now publishing in steroid endocrinology and related fields. It is most appropriate, therefore, that a book should now appear to report on a conference held in their joint honour.

The book starts with two entertaining reviews of the work of Gorski and Jensen - fascinating reading for those involved and historically illuminating for all. There follows a section on the structure and function of the individual steroid receptors. These chapters are easily read and give an interesting reflection of the similarities and differences of the various receptors. It has been clear for a long time that changes in conformation are critical to the function of steroid receptor complexes. The Chapters by Smith, Mendel, Pratt and Auricchio bring us well up to date in this field, being particularly good in defining the interaction of steroid receptors with heat shock protein-90 (originally thought by many to be an artifact but now assuming real importance as a possible regulatory mechanism) and reviewing the physiological significance of tyrosine phosphorylation in steroid receptor function.

For those not strictly interested in steroid endocrin- ology, steroid receptors have had great appeal in two quite separate fields. Firstly, steroid receptors, perhaps more than any other molecule, have given us good information on the control of gene expression in animals. Secondly, steroid receptors have given both prognostic clinical information and the basis for new types of therapy for breast and other steroid hormone sensitive cancers. Readers are provided with several good chapters in both areas. The Chapter by Lannigan and Notides gives a particularly nice view of the 3- dimensional implications of steroid receptor/DNA interaction. One of the most interesting, and rapidly expanding, areas of the steroid receptor industry is the investigation of steroid/growth factor interaction. The Chapter by Stance1 whets the appetite and points the direction for several new research projects. The Chapter from Lippman’s group nicely crosses the bridge from biology to clinic by demonstrating the potential of steroid receptor/growth factor interac- tion to explain the clinical course of breast cancer and suggests how this understanding may lead to improved therapies. The prognostic value of steroid receptors is reviewed by McCarty and new approaches to therapy, such as ‘receptor-directed radiotherapy’ are discussed at the end.

Overall, Sat0 and Stevens have organised this book into an entertaining and very valuable source of information. I feel that it will retain its interest and value for several years and I hope that it will be read by all involved in research in steroid endocrinology, control of gene expression and treatment of breast, gynaecological and prostate cancer.

Robin Leake is in the Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.

Facts and Hypotheses about DNA Methylation DNA Methylation and Gene Regulation (1990). Edited by R. HOLLIDAY, M. MONK AND J. E. PUGH. The Royal Society: London. 161pp. f35. By Peter Karran This volume contains the proceedings of a Discussion Meeting gathered to consider the question of how (or if) methylation of cytosine in DNA regulates gene expression. Epigenetic control of gene expression is clearly a fairly widespread phenomenon and methyl- ation appears to represent the best bet for the underlying mechanism. Although the correlation be- tween high levels of cytosine methylation and reduced transcription have been around for a number of years, enough frustrating exceptions have remained for each of its detailed aspects to prevent general acceptance of a causal relationship between the two phenomena. The authors of the 14 papers which make up this book confront these exceptions in a generally interesting way, although no truly new light is shed on the possible detailed mechanisms of gene repression by methyl- ation.

The scope of the book ranges from a consideration of the possible evolution of methylation as a transcrip- tional repressor for these assorted irrelevant DNA sequences acquired as a consequence of relentless genome expansion to the more common demon- strations of inverse correlations between the levels of cytosine methylation and transcriptional activity. Exemplifying the exceptions to what few general rules have been formulated is the observation that methyl- ation-free CpG islands are not confined to the promoter regions of universally expressed housekeeping genes but may also occur in those of genes expressed in a tissue-specific fashion (Edwards). Also considered (Mehan et al.) are DNA-binding proteins which are methylation-specific but not sequence-specific and which might bind to ‘junk’ DNA, thereby reducing the amount of DNA to be monitored by more fastidious transcription factors. Inactivation of transfected DNA sequences, which is one of the cornerstones of the argument relating methylation in the control of transcription, is also represented here. A series of analogous experiments are described (Frank et al.) in which transfected methylated IgG K genes are ex- pressed only in mature lymphocytes, and are presented as evidence that demethylation is developmentally regulated. There are also two papers which address the question of chromosomal imprinting in mammals in relation to differential methylation patterns in maternal and paternal genes (Monk, Surani). Implicit through- out all the contributions is the idea that methylation is perhaps not the whole story and that some second control system is involved in methylation-related inactivation of transcription. An intriguing possibility is raised (Riggs) that the CpG methylation-associated inactivation of the X-chromosome (perhaps the best

Page 2: Facts and hypotheses about DNA methylation DNA Methylation and Gene Regulation (1990). Edited by R. Holliday, M. Monk and J. E. Pugh. The Royal Society: London. 161pp. £35

example of the correlation between methylation status and gene expression) might in addition be related to a second property of the X-chromosome: its late replication. He also addresses the problem of how methylation initiated at, and migrating from, a single locus can eventually cover the entire X-chromosome. This latter point is also touched upon in the review by Doerfler. Methylation control and epigenetic inheri- tance is reviewed by Holliday along with his attempts to isolate mammalian cell mutants that are defective in DNA methylation. Since the cDNA sequence of the mouse cytosine methyltransferase is now available (Bestor), it is almost certain that experiments using cytosine methyltransferase antisense RNA are under way in various laboratories. These might provide an alternative approach to the selection of mutant mammalian cells.

As a review of the current status of cytosine methylation and gene regulation, I think that this book is recommended reading. I was both informed and entertained. In addition to its well-written contents, the volume is nicely presented (although curiously the price seems to have been omitted). (For the more indigent, it is also available in plain covers in its original form as Proc. Roy. SOC. B 326, pp. 177-338 (1990), its origins explaining the book's annoying double set of page numbers.) I enjoyed it and I look forward to the sequel which might just possibly be entitled 'Control of Gene Regulation by DNA Methylation'.

Peter Karran is at the Imperial Cancer Research Fund, Clare Hall Laboratories, Herts EN6 3LD, I UK.